Methamphetamine abuse continues to increase in the US at alarming rates. Chronic use of this drug can lead to severe neurological and psychiatric impairments as well as to pronounced neurodegenerative changes in humans. The research proposed here is intended to define the molecular cascade leading to microglia activation and subsequent cellular injury following methamphetamine treatment. In this highly focused research project we wish to test the novel hypothesis that methamphetamine exposure leads to the liberation of the monoamine-derived glutamate receptor agonist 2, 4, 5-trihydroxyphenylalanine quinone (TOPA quinone) from catecholaminergic cells, which, in turn interacts with AMPA receptors in microglia. We further hypothesize microglia exposed to TOPA quinone become activated via an AMPA receptor-mediated process and can subsequently induce further cellular damage via a defined molecular cascade. This is an Investigator-Initiated Small Grant (R03) application requesting limited funds to test a defined hypothesis with focused objectives. This is a small, self-contained research project fitting a description for R03 support outlined in NIH announcement PA-06-180. These studies could provide a basis by which therapeutic agents may be used to prevent neuronal injury following methamphetamine exposure. PUBLIC HEALTH RELEVANCE: The research proposed here is intended to define the molecular cascade leading to microglia activation and subsequent neuronal injury following methamphetamine treatment. These studies could provide a basis by which therapeutic agents may be used to prevent neuronal injury following methamphetamine exposure.